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© 2001 American Society for Clinical Oncology Preoperative Chemotherapy in Primary Operable Breast Cancer: Results From the European Organization for Research and Treatment of Cancer Trial 10902ByFrom the European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium; Leiden University Medical Center, Department of Surgery, Leiden, the Netherlands; Centre Henri Becquerel, Department of Surgery, Rouen; and Centre René Huguenin, Department of Medical Oncology, St Cloud, France. Address reprint requests to C.J.H. van de Velde, MD, PhD, Department of Surgery, D6-43, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; email: velde{at}lumc.nl
PURPOSE: To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival (OS) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy. PATIENTS AND METHODS: Six hundred ninety-eight breast cancer patients (T1c, T2, T3, T4b, N0 to 1, and M0) were enrolled onto a randomized phase III trial that compared four cycles of fluorouracil, epirubicin, and cyclophosphamide administered preoperatively versus the same regimen administered postoperatively (the first cycle administered within 36 hours after surgery). Patients were followed up for OS, progression-free survival (PFS), and locoregional recurrence (LRR). RESULTS: At a median follow-up of 56 months, there was no significant difference in terms of OS (hazards ratio, 1.16; P = .38), PFS (hazards ratio, 1.15; P = .27), and time to LRR (hazards ratio, 1.13; P = .61). Fifty-seven patients (23%) were downstaged by the preoperative chemotherapy, whereas 14 patients (18%) underwent mastectomy and not the planned breast-conserving therapy. CONCLUSION: The use of preoperative chemotherapy yields similar results in terms of PFS, OS, and locoregional control compared with conventional postoperative chemotherapy. In addition, preoperative chemotherapy enables more patients to be treated with breast-conserving surgery. Because preoperative chemotherapy does not improve disease outcome compared with postoperative chemotherapy, future trials should involve quality-of-life studies to investigate whether patients will benefit from this treatment modality.
TRIALS THAT STUDIED the role of adjuvant chemotherapy in the management of primary operable breast cancer conducted during the 1970s and 1980s showed significant improvements in progression-free and overall survival.1 Conventionally, adjuvant systemic therapy is administered after local treatment in early breast cancer.2 However, since the introduction of conservative treatment modalities, there has been considerable interest in the efficacy of preoperative chemotherapy to decrease tumor size. One of the potential benefits of preoperative chemotherapy is the more frequent usage of breast-conserving treatment modalities. Moreover, it has been hypothesized that preoperative chemotherapy has a more powerful effect on survival compared with postoperative chemotherapy. The rationale for these hypotheses comes from several biologic premises. Findings in various animal models3-5 showed an increase of labeling index in residual tumor cells as well as an increase of circulating growth-stimulating factors after the removal of the primary tumor in murine models. In these models, adjuvant systemic therapy administered before the removal of the primary tumor impaired this increase in cell-kinetic mechanisms.6,7 In addition, Goldie and Coldman8 developed a hypothesis, which implies that as a tumor cell population increases, an ever-expanding number of drug-resistant phenotypic variants arise as a result of spontaneous somatic mutations. Although the merits of preoperative chemotherapy in the treatment of locally advanced breast cancer are well established, the feasibility of preoperative chemotherapy in early breast cancer is still a matter of discussion. The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Cooperative Group started a randomized trial in 1991 to investigate the value of preoperative chemotherapy in early breast cancer, EORTC trial 10902. The primary objective of this trial was to test whether preoperative chemotherapy yields better results in terms of progression-free and overall survival than the same chemotherapeutic regimen administered postoperatively. Another objective was to study whether preoperative chemotherapy would permit more breast-conserving therapies by reducing primary tumor size. A third objective was to determine whether preoperative chemotherapy resulted in better locoregional control, especially after breast-conserving surgery. An additional objective of the study was to evaluate the response of the primary tumor to preoperative chemotherapy and to correlate this response to disease-free and overall survival. This report compares the outcome of 698 women with early breast cancer randomized to receive either preoperative chemotherapy or the same regimen administered postoperatively.
Patient Characteristics Between April 1991 and May 1999, 698 women were enrolled onto the EORTC study 10902 in 17 institutions in 14 countries. Patients had primary operable breast cancer (T1c, T2, T3, T4b, N0 to 1, and M0). Breast cancer was preferably diagnosed by core needle biopsy (CNB) or by fine-needle aspiration cytology as part of triple diagnosis. For the diagnosis of T1c tumors, CNB was mandatory. CNB was also mandatory in case of doubt or suspicion of carcinoma-in-situ after fine-needle aspiration. Exclusion criteria consisted of age older than 70 years; bilateral breast cancer; previous treatment for breast cancer; presence of distant metastases; pregnancy or lactation at the time of diagnosis; previous or current other malignancies except adequately treated basal or squamous carcinoma of the skin or cervix uteri; World Health Organization performance status more than 2; active cardiac disease; and severe hematologic, renal, or hepatic abnormalities. All patients gave informed consent before entering onto the trial. Randomization was performed centrally by the EORTC Data Center. At randomization, patients were stratified for institution, age (  50 years or > 50 years), clinical tumor size, clinical nodal status (N- or N+), and planned type of surgery (mastectomy or breast-conserving surgery).
Patients 50 years old or younger were considered to be premenopausal, and those older were deemed postmenopausal. Tumor estrogen receptor (ER) status was estimated by the ligand binding assay technique or by the immunohistochemistry technique. For the ligand-binding assay, a concentration
Treatment
Chemotherapy consisted of four cycles of preoperative fluorouracil 600 mg/m2, epirubicin 60 mg/m2, and cyclophosphamide 600 mg/m2 (FEC) administered intravenously, at intervals of every 3 weeks. In the preoperative chemotherapy group, surgical therapy followed within 4 weeks of the fourth course of chemotherapy. In the postoperative chemotherapy group, the first cycle was administered within 36 hours after surgery, as has been advocated before.10,11 Administration of FEC was delayed for a maximum of 2 weeks as a result of either hematologic, hepatic and renal, or gastrointestinal toxicities on day 1 of any cycle. Dose modifications were assessed according to the guidelines stipulated by the EORTC Breast Cancer Cooperative Group.9 Adjuvant radiotherapy was administered after surgery in the preoperative chemotherapy group. In the postoperative chemotherapy group, it was decided to administer irradiation after the completion of chemotherapy. This way, radiotherapy did not interfere with the chemotherapeutic regimen, in which the first course was to be administered preoperatively. All patients who underwent breast-conserving therapy received irradiation of the whole breast. Other recommended guidelines for radiotherapy, as stipulated in the protocol, consisted of chest wall and parasternal irradiation in patients with an initial tumor of 5 cm or more in its largest dimension and irradiation of the infraclavicular and supraclavicular fossa in patients with a positive infraclavicular node after lymph node dissection. Radiotherapy was indicated in all cases where surgery was not considered to be radical. Specified dose at the target volume was 50 gray, administered in four or five weekly fractions in 5 weeks. For the parasternal/infrasupraclavicular fossa and chest wall, at least 45 Gy had to be administered in four or five weekly fractions in 4.5 to 5 weeks. However, some hospitals used their own radiation protocol. Patients
End Points It is well known that the administration of adjuvant chemotherapy is a considerable burden to the patient in terms of quality of life. However, not many data are available that concern the effects of preoperative chemotherapy on quality of life compared with conventional postoperative chemotherapy. Therefore, a quality-of-life study program was set up that was, however, unsuccessful as a result of poor compliance.
Tumor Response
Follow-Up
Statistical Aspects
Patients Of the 698 patients, 350 patients were randomized to receive preoperative chemotherapy, and 348 patients were randomized to the postoperative chemotherapy group (first cycle of FEC administered within 36 hours after surgery). Tumor and patient characteristics were well distributed between the two treatment arms (Table1), except for breast-conserving surgery rates, which were, as expected, higher in the preoperative chemotherapy group. Twenty-one patients were considered ineligible because of inadequate staging (n = 17), a World Health Organization performance status more than 2 (n = 3), or age greater than 70 years (n = 1).
Chemotherapy Overall, 635 patients (91%) received the planned chemotherapy dose (321 patients [92%] in the study arm and 314 patients [90%] in the control arm). Sixty-three patients (8%) received less than 75% of the planned dose. Nineteen patients (3%) who began chemotherapy did not complete it (11 patients [3%] in the study arm and eight patients [2.5%] in the control group). Thirty-eight patients who were randomized to the preoperative chemotherapy group underwent treatment modification because of treatment-related febrile neutropenia versus 44 patients in the postoperative chemotherapy group. No treatment-related deaths were reported. An overview of chemotherapy-related toxicity is given in Table 2. Furthermore, four patients who were randomized to receive postoperative chemotherapy received preoperative chemotherapy, and three patients who were randomized to receive preoperative chemotherapy received postoperative chemotherapy.
Forty patients did not receive chemotherapy. Of these patients, 16 patients were deemed ineligible. Eight patients refused chemotherapeutic treatment, two patients in the postoperative chemotherapy group did not receive chemotherapy as stipulated by the protocol because of postoperative complications, and seven patients did not receive chemotherapy for unknown reasons. From a further seven patients, no information that concerned treatment specifications or follow-up was received, even after repeated queries.
Unfortunately, for approximately 30% of the patients, information that concerned ER status was missing. This was partly a result of the fact that this information was not mandatory and that tamoxifen was given irrespective of ER status in patients
Surgery In the preoperative chemotherapy group, 20 patients did not receive the surgical treatment stipulated by the study protocol, versus 14 patients in the postoperative group. At the time of axillary clearance, at least six nodes had to be obtained for pathologic examination, and in 77% of the patients entered onto the study, 10 or more axillary nodes were examined. Surgical complications consisted of 16 grade 1/2 wound infections in the preoperative chemotherapy group, versus 25 grade 1/2 wound infections and two grade 3/4 wound infections in the postoperative chemotherapy group that required antibiotic treatment. Anticoagulant prophylaxis was administered on the basis of experience from previous trials that studied the efficacy of perioperative chemotherapy.13,14 No severe postsurgical thromboembolic complications were observed in the postoperative chemotherapy group.
Overall Survival, Progression-Free Survival, and Locoregional Recurrence
Subgroup analyses were performed in an exploratory way for nodal status and menopausal status. The largest difference was found in clinical node-negative patients (n = 385) in terms of overall survival (HR, 1.77; 95% CI, 1.03 to 3.02; P = .04) and progression-free survival (HR, 1.53; 95% CI, 1.03 to 2.28; P = .03) in favor of the postoperative chemotherapy group. These P values failed to be significant compared with the adjusted nominal significance level of .0125.
Tumor Response
Table 4 shows the correlation between clinical tumor size before preoperative chemotherapy and pathologic tumor size after preoperative chemotherapy. Both in the preoperative and postoperative arms, 14% of the patients had a clinical tumor size less than 2 cm at the time of diagnosis. After four courses of preoperative chemotherapy, 47% of the patients had a pathologic tumor size less than 2 cm, whereas 26% of the patients in the postoperative arm had a pathologic tumor size less than 2 cm.
Nodal status characteristics are listed in Table 5. At the time of diagnosis, 49% of the patients in the preoperative group and 47% of the patients in the postoperative group had clinical negative axillary lymph nodes. Pathologic examination after surgery showed a lower percentage of negative axillary lymph nodes in both the preoperative and the postoperative group 38% and 35%, respectively. Differences in pathologic tumor size and axillary nodal status between both study arms are listed in Table 6 and Table 7.
Downstaging Before treatment, investigators had to report whether mastectomy or breast-conserving surgery was indicated. In the preoperative chemotherapy group, the rate of breast-conserving therapy was higher than in the postoperative chemotherapy group. In the preoperative chemotherapy group, 57 patients (23%) underwent breast-conserving surgery and not the planned mastectomy (Table 8), versus 14 patients (18%) who underwent mastectomy and not the planned breast-conserving surgery.
In the preoperative chemotherapy group, all patients who underwent breast-conserving surgery were compared according to their planned type of surgery. Patients who were planned for mastectomy but underwent breast-conserving therapy because of downstaging of the tumor did worse in terms of overall survival (HR, 2.53; 95% CI, 1.02 to 6.25) compared with patients who were initially planned to receive breast-conserving therapy and were treated accordingly (Fig 4), which suggested a relation between the outcome of locoregional treatment and tumor response.
This, however, is not a randomized comparison. The observed difference in disease outcome might be a result of a selection bias as a result of different patient characteristics in the two groups. Therefore, we evaluated patient characteristics to detect potential differences. Of the patients who were downstaged, 35% were clinically node-negative before the start of chemotherapy versus 46% in the group in which breast-conserving therapy was already indicated before the administration of chemotherapy. After chemotherapy, the pathologic node-negative rates were 63% and 51%, respectively. This indicates that axillary nodal response to preoperative chemotherapy was actually better in downstaged patients than in the others who underwent breast-conserving surgery. Remarkably, there was an obvious similarity in both clinical tumor size before preoperative chemotherapy and pathologic tumor size between the two groups (Table 9). These differences may well be a result of differences in initial tumor-node-metastasis system classification between both of these patient groups. However, the fact that clinical T and N stages were to a large extent similar does not support this hypothesis. Conclusively, these findings do support the assumption that radical conservative surgery, especially after downstaging, may be more difficult because of the fact that tumor-free margins are more difficult to assess after preoperative chemotherapy.
Quality of Life Unfortunately, only one institution has collected quality-of-life data on a total number of 20 patients. These data are insufficient to report here or to draw any conclusion on the effect of preoperative chemotherapy on quality of life.
In 1986, the Breast Cancer Cooperative Group started a trial to study the effectiveness of one course of fluorouracil, doxorubicin, and cyclophosphamide administered perioperatively within 36 hours after surgery in early breast cancer patients. This regimen resulted in significantly improved locoregional control and disease-free survival rates.10 Therefore, the logical next step was to start a trial that would study the qualities of preoperative chemotherapy. EORTC trial 10902 was designed to address whether preoperative chemotherapy yields the same or better results in terms of overall and disease-free survival compared with the same type of chemotherapy administered postoperatively and whether preoperative chemotherapy allows more breast-conserving therapies. A third objective was to assess the value of tumor response to preoperative chemotherapy as a predictor of disease outcome. Several randomized, clinical, phase III trials that compared postoperative adjuvant chemotherapy and preoperative chemotherapy were performed in the past two and a half decades. These trials have been listed in Tables 10 to 12. A comparison of the results of these trials is difficult because of the fact that the study protocols differ substantially in design and chemotherapeutic regimen. However, to date none of these trials, including EORTC trial 10902, has been able to show a positive effect of preoperative chemotherapy in terms of progression-free or overall survival. Two trials, conducted by Mauriac and Scholl15-20 initially reported a significant positive effect of preoperative chemotherapy on progression-free and overall survival, but after a longer period of follow-up, the significant benefit of preoperative chemotherapy on survival had disappeared. In addition, in the Mauriac trial, locoregional control was worse in the preoperative arm compared with the standard arm.
Of the trials listed in Tables 10 through 12, the National Surgical Adjuvant Breast and Bowel Project B-1821,22 trial is similar in terms of study design to the EORTC trial. Fisher et al21,22 studied the efficacy of four courses of preoperative doxorubicin and cyclophosphamide in 1,523 women with primary operable breast cancer. Contrary to the EORTC trial, the first course of postoperative chemotherapy was not administered directly after surgery. Overall survival, progression-free survival, and recurrence rates were not significantly different between the study and the postoperative population. Interestingly, the authors observed a significantly higher rate of ipsilateral breast recurrences in patients who underwent a lumpectomy as a result of downstaging compared with the rate in patients who underwent a lumpectomy as planned. We observed a similar effect on overall survival in patients who underwent breast-conserving surgery as a result of downstaging. However, we did not find such an effect on locoregional recurrence rates.
Nevertheless, these results demonstrate an important potential danger induced by tumor downstaging. Even if clinical assessment of tumor response demonstrates tumor shrinkage as a result of chemotherapy, there is no absolute proof that the tumor has actually shrunken in size. Several authors demonstrated a loss of density in tumors treated by chemotherapy but no shrinkage.23-25 In our trial, the mammographies before and after preoperative chemotherapy of 83 patients were revised and correlated with histologic data, and a similar effect on the assessment of tumor response was found (data not shown). Thus, treating downstaged tumors with more breast-conserving modalities may result in a higher false-negative rate of tumor-negative surgical margins. In the B18 trial, a clinical overall response was seen in 79%, whereas 35% of the preoperative chemotherapy group experienced a cCR. A pCR, however, occurred in only 9% of these patients. Disease-free, relapse-free, distant disease-free, and overall survival were better in women whose tumors showed a pCR compared with those patients with residual disease. This is in accordance with the results from the EORTC 10902 study and the experience of other investigators.19,26 In the EORTC trial, tumor response to preoperative chemotherapy was low in comparison with the response rates described in the literature.15-22,26-36 Clinical overall tumor responses after four to six cycles of preoperative polychemotherapy range approximately between 65% and 90%. The cCR rates vary between 10% and 30%. However, the pCR rate usually is much lower, resulting in a poor correlation. Controversially, in the EORTC 10902, trial 49% of the patients who received preoperative chemotherapy experienced a clinical overall response as assessed by palpation and 7% of the study-population had a cCR. The remarkable discrepancy between our results and those of other authors is difficult to explain. The vast majority of patients received the chemotherapeutic dose stipulated by the protocol, ie, four courses of FEC containing epirubicin 60 mg/m2, which means that the regimen was well tolerated. Now, one could argue that total cumulative doses of epirubicin lower than 300 mg/m2 are suboptimal. However, higher doses of epirubicin in a combined chemotherapy schedule have so far not been demonstrated to be more effective in terms of overall or relapse-free survival in primary operable breast cancer.37-40 Several studies23-25 have addressed this discrepancy between cCR and pCR and compared clinical measurements with mammographic and ultrasonographic measurements. These studies generally demonstrate an overestimation of tumor response by palpation alone. In the majority of clinical trials that study the effects of preoperative chemotherapy, clinical measurements are commonly used to assess the amount of tumor response, as described by the guidelines of the International Union Against Cancer. In EORTC trial 10902, tumor response was measured by using the data of both palpation and mammographic tumor measurements. Unfortunately, we were not able to demonstrate this confounding error induced by using palpation measurements alone because of a poor registration of measurements. Conclusively, mammographic measurements should be implemented in the assessment of tumor response on a standard basis to give an objective idea of the degree of tumor response. Moreover, in the case of a cCR, it may be helpful to perform ultrasonography in selecting those patients who do not require surgery after preoperative chemotherapy and in localizing abnormalities in those who do.41,42 In locally advanced and primary inoperable breast cancer, the purpose of preoperative treatment is to enable adequate local treatment, favorably leading to breast conservation. In patients with stage I or II breast cancer who are candidates for breast-conserving therapy irrespective of preoperative chemotherapy, the goal of preoperative chemotherapy is unclear. Some investigators argue that tumor response to preoperative chemotherapy is an independent predictor of treatment outcome. Therefore, it could be of benefit for breast cancer patients to adjust systemic adjuvant treatment at an early stage if tumor response to preoperative chemotherapy is inadequate. Controversially, preoperative chemotherapy might lead to overtreatment of breast cancer patients. This can be explained by the fact that patients receive systemic treatment regardless of histologic staging of the tumor and axillary nodal status. The breast-conserving therapy rate was higher in the preoperative chemotherapy group in comparison with the postoperative chemotherapy group. This finding, together with the equal locoregional control rate in both groups, advocates the advantageous role of primary chemotherapy in breast-conserving management. On the other hand, 14% of patients who initially were supposed to undergo breast-conserving surgery received a modified radical mastectomy. This suggests that a delay in surgical treatment as a result of the use of primary chemotherapy can result in a more aggressive type of surgical management of breast cancer in a considerable number of patients. In addition, a hypothesis-generating analysis that compared survival rates of patients who underwent breast-conserving surgery as a result of downstaging of the tumor with patients who underwent breast-conserving surgery as initially was planned showed a favorable trend for the latter group of patients. Therefore, it can be hypothesized that patient prognosis is determined by the initial tumor stage and not tumor stage after preoperative chemotherapy. The idea that changes in surgical management after preoperative chemotherapy are solely because of either increase or decrease of tumor volume is arguable. Because preoperative chemotherapeutic regimens take approximately 3 months to complete, patient or doctor surgical preferences may be altered for subjective reasons during this period of time. The use of preoperative or primary chemotherapy was introduced approximately three decades ago in locally advanced breast cancer. Since then, its role in the management of locally advanced breast cancer has been firmly established. However, the advantages are not clear in early breast cancer. Despite the fact that preoperative chemotherapy may permit more breast-conserving treatment modalities, there may be problems, for instance in achieving adequate locoregional control as a result of the difficulty of assessing tumor margins after the administration of preoperative chemotherapy. Moreover, it has become clear that the supposed survival benefits of preoperative chemotherapy based on preclinical data are not exerted in primary operable breast cancer patients. Although benefits of preoperative chemotherapy in early breast cancer patients are less clear compared with the locally advanced breast cancer patients, the potential to enhance breast-conserving therapy makes it an attractive treatment modality. Postmenopausal early breast cancer patients especially might benefit from preoperative chemotherapy, although preoperative chemotherapy may be less beneficial for young breast cancer patients who are at a higher risk of recurrence of disease, especially after primary conservative therapy. Although this trial did not show such differences (data not shown), other investigators have found young age to be a strong independent prognostic factor for recurrence after breast-conserving therapy.11,43,44 Moreover, the possibility of studying the effects of chemotherapy on well-established tumor characteristics as well as experimental tumor markers makes chemotherapy in the preoperative setting highly attractive for translational research purposes.45 The comparison of core needle biopsies with the same tumor after systemic treatment is a worthwhile reason to continue preoperative chemotherapy trials in early breast cancer. Unfortunately, not many data concerning quality-of-life issues in relation to preoperative chemotherapy are available in the literature. Quality-of-life studies, however, have been performed to investigate the effects of breast-conserving therapy versus mastectomy and fail to show a clear benefit for the conservative treatment modality, except for a slightly less impaired body image.46-49 Considering the fact that preoperative as well as postoperative chemotherapy seems to yield similar results in terms of prognosis, this might be a conclusive factor on the decision of which chemotherapeutic strategy should be chosen. Therefore, the role of preoperative chemotherapy should be studied in future trials that focus on translational research, equivalence, quality of life, and local control, rather than trying to detect overall and progression-free survival differences.
Federal Republic of Yugoslavia, C.J.H. van de Velde, M.A. Nooy, Hopital Cantonal Universitaire de Country, Principal Investigator, Institution France, J.-P. Julien, Centre Henri Becquerel, Rouen M. Tubiana-Hulin, F. Bachelot, Centre René Huguenin, St Cloud, T. Delozier, Centre Regional François Baclesse, Caen Netherlands, C.J.H. van de Velde, M.A. Nooy, Leiden University Medical Center, Leiden Switzerland, H. Bonnefoi, Hopital Cantonal Universitaire de Geneve, Geneva Republic of South Africa, J.A. van Zyl, A.G. Muller, University of Stellenbosch, Tygerberg Hospital, Tygerberg Egypt, S. Omar, National Cancer Institute, Cairo Poland, J. Jassem, J. Jaskiewicz, Medical University of Gdansk, Gdansk Spain, J.J. Grau, Hospital Clinico y Provencial de Barcelona, Barcelona Federal Republic of Yugoslavia, D. Vukotic, Institute of Oncology and Radiology, Belgrade Slovenia, T. Cufer, M. Snoj, The Institute of Oncology, Ljubljana Russia, O. Ivanova, V.F. Semiglazov, Petrov Research Institute of Oncology, St Petersburg Greece, I. Varthalitis, Evangelismos Hospital, Athens Saudi Arabia, A. Ezzat, King Faisal Spec. Hospital and Research Center, Riyadh
Supported by an educational grant from Pharmacia & Upjohn, Peapack, NJ, and a personal grant from the Dutch Cancer Society NKB/KWF, Amsterdam, the Netherlands. We thank Marc J. van de Vijver, MD, PhD, and Pieter C. Clahsen, MD, PhD, for thoroughly reading the manuscript and giving their valuable advice and criticism.
1. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352: 930-942, 1998[Medline]
2.
Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 90: 1601-1608, 1998
3.
Gunduz N, Fisher B, Saffer E: Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res 39: 3861-3865, 1979 4. Fisher B, Gebhardt M, Saffer E: Further observations on the inhibition of tumor growth by C. parvum with cyclophosphamide: VII. Effect of treatment prior to primary tumor removal on the growth of distant tumor. Cancer 43: 451-458, 1979[Medline]
5.
Fisher B, Gunduz N, Saffer E: Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth metastases. Cancer Res 43: 1488-1492, 1983
6.
Fisher B, Gunduz N, Coyle J, et al: Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 49: 1996-2001, 1989
7.
Fisher B, Saffer E, Rudock C, et al: Effect of local or systemic treatment prior to primary tumor removal on the production and response to a serum growth-stimulating factor in mice. Cancer Res 49: 2002-2004, 1989 8. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63: 1727-1733, 1979[Medline] 9. EORTC Breast Cancer Cooperative Group: Manual for Clinical Research in Breast Cancer. Almere the Netherlands, Excerpta Medica, 1998, pp 96-97
10.
Clahsen PC, van de Velde CJH, Julien JP, et al: Improved local control and disease-free survival after perioperative chemotherapy for early-stage breast cancer. J Clin Oncol 14: 745-753, 1996
11.
Elkhuizen PH, van Slooten HJ, Clahsen PC, et al: High local recurrence risk after breast-conserving therapy in node-negative premenopausal breast cancer patients is greatly reduced by one course of perioperative chemotherapy: A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group Study. J Clin Oncol 18: 1075-1083, 2000 12. Hayward JL, Carbone PP, Heuson JC, et al: Assessment of response to therapy in advanced breast cancer. Br J Cancer 35: 292-298, 1977[Medline]
13.
Clahsen PC, van de Velde CJH, Julien JP, et al: Thromboembolic complications after perioperative chemotherapy in women with early breast cancer. J Clin Oncol 12: 1266-1271, 1994 14. Ludwig Breast Cancer Study Group: Toxic effects of early adjuvant chemotherapy for breast cancer. Lancet 2: 542-544, 1983[Medline]
15.
Mauriac L, Durand M, Avril A, et al: Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Ann Oncol 2: 347-354, 1991
16.
Mauriac L, MacGrogan G, Avril A, et al: Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: A unicentre randomized trial with a 124-month median follow-up. Ann Oncol 10: 47-52, 1999 17. Scholl SM, Asselain B, Palangie T, et al: Neoadjuvant chemotherapy in operable breast cancer. Eur J Cancer 27: 1668-1671, 1991 18. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumors considered too large for breast conserving surgery: Preliminary results of a randomized trial—S6. Eur J Cancer 30A: 645-652, 1994 19. Scholl SM, Pierga JY, Asselain B, et al: Breast tumor response to primary chemotherapy predicts local and distant control as well as survival. Eur J Cancer 31A: 1969-1975, 1995 20. Broët P, Shcoll SM, De la Rochefordiere A, et al: Short and long term effects on survival in breast cancer patients treated by primary chemotherapy: An updated analysis of a randomized trial. Breast Cancer Res Treat 58: 151-156, 1999[Medline]
21.
Fisher B, Brown A, Mamounas E, et al: Effect of pre-operative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15: 2483-2493, 1997 22. Fisher B, Bryant J, Wolmark N, et al: Effect of pre-operative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16: 2672-2685, 1998[Abstract] 23. Moskovic EC, Mansi JL, King DM, et al: Mammography in the assessment of response to medical treatment of large primary breast cancer. Clin Radiol 47: 339-344, 1993[Medline]
24.
Helvie MA, Joynt LK, Cody RL, et al: Locally advanced breast carcinoma: Accuracy of mammography versus clinical examination in the prediction of residual disease after chemotherapy. Radiology 198: 327-332, 1996
25.
Vinnicombe SJ, MacVicar AD, Guy R, et al: Primary breast cancer: Mammographic changes after neoadjuvant chemotherapy, with pathologic correlation. Radiology 198: 333-340, 1996
26.
Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17: 460-469, 1999
27.
Semiglazov VF, Topuzov EE, Bavli JL, et al: Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer. Ann Oncol 5: 591-595, 1994
28.
Powles TJ, Hickish TF, Makris A: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 13: 547-552, 1995
29.
Makris A, Powles TJ, Ashley SE, et al: A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in breast cancer. Ann Oncol 9: 1179-1184, 1998 30. Gardin G, Rosso R, Campora E, et al: Locally advanced non-metastatic breast cancer: Analysis of prognostic factors in 125 patients homogeneously treated with a combined modality approach. Eur J Cancer 31A: 1428-1433, 1995 31. Cocconi G, di Blasio B, Bisagni G, et al: Neoadjuvant chemotherapy or chemotherapy and endocrine therapy in locally advanced breast carcinoma. Am J Clin Oncol 13: 226-232, 1990[Medline] 32. Hortobagyi GN, Blumenschein GR, Spanos W, et al: Multimodal treatment of loco-regionally advanced breast cancer. Cancer 51: 763-768, 1983[Medline]
33.
von Minckwitz G, Costa SD, Eiermann W, et al: Maximized reduction of primary breast tumor size using pre-operative chemotherapy with doxorubicin and docetaxel. J Clin Oncol 17: 1999-2005, 1999
34.
Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy in operable breast cancer: Eight-year experience at the Milan Cancer Institute. J Clin Oncol 16: 93-100, 1998
35.
Bonadonna G, Veronesi U, Brambilla C, et al: Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. J Natl Cancer Inst 82: 1539-1545, 1990 36. Belembaogo E, Feillel V, Chollet P, et al: Neoadjuvant chemotherapy in 126 operable breast cancers. Eur J Cancer 28A: 896-900, 1992
37.
Biganzoli L, Piccart MJ: The bigger the better? . . . or what we know and what we still need to learn about anthracycline dose per course, dose intensity and cumulative dose in the treatment of breast cancer. Ann Oncol 8: 1177-1182, 1997
38.
Bastholt L, Dalmark M, Gjedde SB, et al: Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: A randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperaive Group. J Clin Oncol 14: 1146-1155, 1996 39. Rodenhuis S, Richel DJ, van der Wall E, et al: Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet 352: 515-521, 1998[Medline] 40. Valagussa P, Bonadonna G: Epirubicin in the primary chemotherapy of breast cancer, in Bumma S, Airoldi M (eds): High Dose Epirubicin in Breast Cancer. Torino Italy, Archimedica, 1998, pp 31-40 41. Herrada J, Iyer RB, Atkinson EN, et al: Relative value of physical examination, mammography, and breast sonography in evaluating the size of the primary tumor and regional lymph node metastases in women receiving neoadjuvant chemotherapy for locally advanced breast carcinoma. Clin Cancer Res 3: 1565-1569, 1997[Abstract] 42. Seymour MT, Moskovic EC, Walsh G, et al: Ultrasound assessment of residual abnormalities following primary chemotherapy for breast cancer. Br J Cancer 76: 371-376, 1997[Medline]
43.
Kroman N, Jensen M-B, Wohlfahrt J, et al: Factors influencing the effect of age on prognosis in breast cancer: Population based study. BMJ 320: 474-479, 2000 44. Elkhuizen PHM, Voogd AC, van den Broek LCJM, et al: Risk factors for local recurrence after BCT for invasive carcinomas: A case-control study of histological factors and alterations in oncogene expression. Int J Rab Oncol Biol Phys 45: 73-83, 1999 45. Clahsen PC, van de Velde CJH, Duval C, et al: The utility of mitotic index, estrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer. Eur J Surg Cancer 2: 356-363, 1999 46. Moyer A: Psychosocial outcomes of breast-conserving surgery versus mastectomy: A meta-analytic review. Health Psychol 16: 284-298, 1997[Medline] 47. Poulsen B, Graversen HP, Beckmann J, et al: A comparative study of post-operative psychosocial function in women with primary operable breast cancer randomized to breast conservation therapy or mastectomy. Eur J Surg Cancer 23: 327-334, 1997 48. Irwig L, Bennets A: Quality of life after breast conservation or mastectomy: A systematic review. Aust N Z J Surg 67: 750-754, 1997[Medline] 49. Whelan T, Levine M, Julian J, et al: The effects of radiation therapy on quality of life of women with breast carcinoma: Results of a randomized trial—Ontario Clinical Oncology Group. Cancer 88: 2260-2266, 2000[Medline] Submitted September 26, 2000; accepted June 29, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 fmol ER/mg protein was considered positive, and a value lower than 10 fmol ER/mg protein was considered negative. If the ER status was measured by immunohistochemistry, positivity or negativity was determined according to the scoring systems used by the individual institutions. There was no standardization of the assay, so general cutoff points cannot be given for immunohistochemistry (EORTC Manual for Clinical Research in Breast Cancer).
